Phosphorus is an essential element in human nutrition and plays essential structural and functional roles in the biochemistry, cellular integrity, and physiological processes of the body. In foods comprising animal or vegetable matter, phosphorus can be found as inorganic phosphate (Pi) (e.g., in its pentavalent form in combination with oxygen as phosphate (PO43−)), which can be readily absorbed from the gastrointestinal tract. Also, phosphate can be found as a constituent of bio-macromolecules such as proteins, nucleic acids, lipids and sugars. Plant material can also be enriched in phytic acid (C6H6[OPO(OH)2]6), which is the principal storage form of phosphate (phytic phosphate) in many plant tissues (e.g., bran and seeds), accounting for 70% to 80% of phosphate in plants. Phytic acid or salts thereof (phytate) typically cannot be absorbed by monogastric animals and will pass out with the feces. Phytic acid/phytate can account for approximately 25% of an adult's daily dietary phosphate intake.
Phosphate is an essential component of bone mineral, as approximately 85% of phosphate in the adult body is in mineralized extracellular matrix, such as bone and teeth. Approximately 15% of phosphate is intracellular (e.g., in soft tissues) and about 0.1% is found in extracellular fluids (Tenenhouse et al., Vitamin D, 2nd edition, Elsevier, 2005). Cellular phosphate can also be found in the form of phospholipids which make up the structure of cellular membranes. Phosphate is also an essential structural component of nucleic acids such as DNA and RNA as well as nucleotides such as adenosine triphosphate (ATP) which is an important energy storage and transfer molecule and cyclic adenosine monophosphate which is an important cellular signaling molecule. Other physiological functions of intracellular phosphate include the following: (1) phosphorylation of a number of protein enzymes, hormones and cell signaling molecules for their activation; (2) maintaining normal acid-base balance as a physiological buffer; and (3) comprising the phosphate-containing molecule 2,3-diphosphoglycerate (2,3-DPG) in red blood cells. An average human contains about 700 to 1,000 grams of phosphorus (Lau K., Phosphate Disorders. Saunders; 1986:398-470), and consumes and excretes about one gram to about three grams of phosphorus per day in the form of PO43−.
Humans maintain phosphate homeostasis by at least three routes—the gastrointestinal tract, kidneys, and bone. The gastrointestinal tract participates in phosphate homeostasis as an organ of phosphate absorption and excretion/resorption. Bone serves as a reservoir of phosphate which can be mobilized in response to various physiological signals. Gastrointestinal absorption of dietary phosphate is very efficient, with the principal sites of absorption being the duodenum and the jejunum (Delmez J A et al., Am J Kidney Dis, 1992, 19:303-317). A variable amount of dietary phosphate (10% to 80% of the ingested amount) is excreted in feces, depending on whether the diet is of plant origin (largely inaccessible phosphate) or animal tissue origin (largely digestible). Inorganic phosphate in food is absorbed in two ways, an active transcellular route via the brush border membrane and a passive paracellular route via tight junctions between cells (Cross et al., Miner Electrolyte Metab 1990, 16:115-124, and Walton J et al., Clin Sci 1979, 56:407-412). Some reports based on rat studies indicate that colonic phosphate transport is mediated mainly through the paracellular diffusive pathway (Hu et al., Miner Electrolyte Metab, 1997, 23:7-12; and Peters et al., Res Exp Med (Berl), 1988, 188:139-149). Other reports based on rat studies suggest that transcellular active transport is the dominant route in phosphate absorption across small intestine (Eto et al., Drug Metab Pharmacokinet, 2006, 21:217-221).
The kidney participates in phosphate homeostasis as an organ of phosphate filtration, reabsorption and excretion. The kidney is the main regulatory organ that maintains phosphate homeostasis. In healthy adult individuals, daily renal phosphate excretion equals the amount of daily gastrointestinal phosphate absorption. However, in states of phosphate depletion, the kidneys reduce urinary phosphate excretion to virtually zero (Knox F et al., Am. J. Physiol. 1977, 233:F261-F268). Renal phosphate reabsorption occurs mainly in the proximal tubule. The fractional urinary excretion of phosphate can vary between 0.1% to 20%, thus representing a powerful homeostatic mechanism. In severe renal failure, such as that resulting from chronic kidney disease, hyperphosphatemia occurs from inadequate renal phosphate clearance.
Primary regulatory factors of phosphate homeostasis are serum phosphate and parathyroid hormone (PTH). Increased serum phosphate levels enhance urinary excretion of phosphate. PTH decreases tubular phosphate reabsorption and increasing excretion of soluble phosphate into the urine. Other factors that affect phosphate homeostasis include, but are not limited to, age, diet (i.e. amount of phosphate ingested and/or chemical form of phosphate ingested), disease, pharmaceutical agents and diurnal variation.
Vitamin D, especially its active form 1,25-dihydroxyvitamin D (also called calcitriol), can also affect phosphate homeostasis by directly stimulating intestinal absorption of phosphate. In addition, vitamin D enhances bone resorption through mobilization of calcium and phosphate into the plasma (Albaaj F & Hutchison A, Drugs 2003, 63:577-596).
An example of abnormal phosphate homeostasis is hyperphosphatemia, which can occur by one or more of the following three mechanisms. The first mechanism is excessive phosphate absorption. The second mechanism is decreased phosphate excretion. The third mechanism is shifting phosphate from intracellular spaces to extracellular spaces. Severe hyperphosphatemia can cause paralysis, convulsions and cardiac arrest. Hyperphosphatemia occurs at serum phosphate concentrations above 5 mg/dl, which is associated with an increased risk of death (Block G et al., J. Am. Soc. Nephrol. 2004, 15:2208-2218). A normal physiological serum phosphate concentration is generally considered to be a serum phosphate concentration between about 2.4 mg/dl to about 4.5 mg/dl (Block G & Port F, Am. J. Kidney Dis. 2000, 35:1226-1237).
Patients with impaired kidney function can develop hyperphosphatemia as a result of decreased phosphate excretion by the kidney. Hyperphosphatemia ensues either when the vascular supply to the kidneys becomes reduced or when the glomeruli become damaged and cease filtering phosphate from the blood. As such, hyperphosphatemia is a predictable consequence of kidney disease and most kidney disease patients either have or will develop hyperphosphatemia. Examples of such kidney diseases include, but are not limited to, end stage renal disease, acute renal failure, chronic renal failure, polycystic kidney disease, chronic kidney disease, acute tubular necrosis (e.g., renal artery stenosis), infections that reduce kidney function (e.g., septicemia or kidney infection such as acute pyelonephritis), kidney transplantation rejection, and urinary tract obstruction.
Hyperphosphatemia associated with chronic kidney disease leads to severe pathophysiologies in calcium and phosphate homeostasis, especially if present over extended periods of time. Such pathophysiologies include, but are not limited to, hyperparathyroidism, bone disease (e.g., renal osteodystrophy) and calcification in joints, lungs, eyes and vasculature. Hyperphosphatemia in patients with chronic kidney disease is independently associated with mortality risk and the exact mechanism by which hyperphosphatemia increases mortality risk is unknown. For individuals who exhibit renal insufficiency, an elevation of serum phosphate within the normal range has been associated with progression of renal failure and increased risk of cardiovascular events. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease recommends maintenance of serum phosphate below 5.5 mg/dl, calcium-phosphate (Ca X P) product less than 55 mg2/dl2, and intact parathyroid hormone (iPTH) between 150 pg/ml and 300 pg/ml. Although the etiology is not fully demonstrated, high calcium-phosphate product has been held responsible for soft tissue calcification and cardiovascular disease. Cardiovascular disease is the cause of death in almost half of all dialysis patients.
Many kidney disease patients need to take an active form of vitamin D such as 1α,25-dihydroxyvitamin D3 for maintaining calcium homeostasis and/or for treating or preventing hypocalcemia and/or secondary hyperparathyroidism because these patients are deficient in active vitamin D. Vitamin D3 is first metabolized to 25-hydroxyvitamin D3 (also called calcidiol) in the liver and subsequently to 1α,25-dihydroxyvitamin D3 in the kidney. 1α,25-dihydroxyvitamin D3 is much more active than 25-hydroxyvitamin D3. Kidneys with impaired function cannot convert 25-hydroxyvitamin D3 to 1α,25-dihydroxyvitamin D3. The low 1α,25-dihydroxyvitamin D3 level stimulates the parathyroid gland to secret more PTH and parathyroid hyperplasia and secondary hyperparathyroidism ensue. Standard treatment of secondary hyperparathyroidism in individuals with chronic kidney disease includes active vitamin D or its analogs. Likewise, approximately 70% of individuals with end stage renal disease or failure receive some form of vitamin D. As discussed above, vitamin D stimulates intestinal absorption of phosphate. Therefore, kidney disease patients who take vitamin D such as 1α,25-dihydroxyvitamin D3 are more susceptible to hyperphosphatemia and can also have their existing hyperphosphatemia exacerbated due to a combination of increased phosphate absorption with concomitant decreased phosphate excretion.
Therapeutic efforts to reduce serum phosphate levels include, but are not limited to, dialysis, reduction in dietary phosphate intake, administration of nicotinamide, and oral administration of insoluble phosphate binders. Examples of insoluble phosphate binders include, but are not limited to, aluminum compounds (e.g., Amphojel® aluminum hydroxide gel), calcium compounds (e.g., calcium carbonate, acetate such as PhosLo® calcium acetate tablets, citrate, alginate, and ketoacid salts), anion exchange polymers (e.g., amine functional polymers described in U.S. Pat. Nos. 5,985,938, 5,980,881, 6,180,094, 6,423,754, and PCT publication WO 95/05184, Dowex® anion-exchange resins in the chloride form, RenaGel®, and polymer bound guanidinium hydrochloride), inorganic compounds such as lanthanum carbonate tetrahydrate (Fosrenal™), ferric salts of citrate and acetate, and a lanthanum based porous ceramic material (RenaZorb™).